Frontiers in Incidental Findings

1. Canada Research Chair in Neuroethics Professor of Neurology National Core for Neuroethics University of British Columbia Presidential Commission for the Study of Bioethical Issues February 2011 Frontiers in Incidental Findings Judy Illes, Ph.D.

2. Agenda Background Current landscape Ongoing discovery Uncharted territory

3. Agenda Background Current landscape Ongoing discovery Uncharted territory

4. Incidental Findings Findings unrelated to the purpose of a research study or clinical examination

5. Case Study in Neuroimaging MK is a medical student conducting functional MRI research for his PhD on memory. He has been a mentor to the incoming medical student class. Two weeks into the program SH, a new medical student, enthusiastically enrolls in MK’s study. On the anatomy pre-scan, MK notices an anomaly in SH’s prefrontal cortex. There is no institutional protocol in place. What should he do?

6. Real people, real problems • Potentially significant disorders of the CNS • Psychological and financial cost • Risk to personal health care security • Relevance to third parties • Trust and reciprocity • Cost to the research enterprise • Increasing applications of neuroimaging • Expanding requirements for biobanks and data sharing Fundamental Issues

7. Agenda Background Current landscape Ongoing discovery Uncharted territory

8. Structural Anomalies Meningioma Cavernous hemangioma AVM Mucous plug

9. Frequency Overall occurrence of anomalies in adults and children: 18%-20% (one in every five people scanned) vascular and tumours Clinically significant findings requiring follow-up: 2%-8%

10. Routine Urgent Associations with Age high Frequency low young old Age Illes et al., Neurology, 2008

11. Management Strategies Personnel conducting scans Neuroradiological review Illes et al., JMRI, 2004 Racine et al., BMC Ethics, 2010

12. Subjects’ Expectations Kirschen et al., JMRI, 2006

13. The Challenge Illes, Nature Clinical Neurology, 2006; Illes et al., Neurology, 2008

14. C Research Study Incidental finding is detected All scans reviewed Principal investigator or designate Physician qualified to read scans D Incidental finding is evaluated Principal investigator or designate No action taken Incidental finding is communicated Research subject or surrogate is encouraged to initiate clinical follow-up A Research protocol anticipates incidental findings B IRB protocol & informed consent articulate plan for managing incidental findings Subject option to decline to be informed Incidental findings are managed Incidental findings are not managed Illes et al., based on Science 2006, Neurology 2008

15. Agenda Background Current landscape Ongoing discovery Uncharted territory

16. Economic Analysis Cost implications of managing incidentally found intracranial aneurysms Mathematical modeling of four strategies for different populations of human subjects Sadatsafavi et al., Value in Health, 2010

17. Four Different Strategies 1. No screening, no further workup 2. MRI read by researcher not trained in clinical neuroimaging If suspicious: read by specialist If suspicious: MR Angiography (MRA) 3. MRI read by specialist If suspicious: MRA 4. Full clinical-grade work-up in all participants

18. Best Economic Strategy per Subgroup

19. Implications for Management A shift from researcher-focused to participant-focused decision-making for incidental findings Initial screening by a non-trained researcher is not cost-effective for any subgroup A customized strategy is essential Optimal strategy is affected by variables at time of screening: age group, gender, family history Exclusion of certain participant groups may be justified when weighing risk and cost of screening

20. An emerging approach to the study of genetic variations and functional brain responses • Brain activation patterns and the course of cognitive decline in people with AD susceptibility genes • COMT gene polymorphism and prefrontal dopamine regulation with genetic risk of schizophrenia •  5-HTT serotonin transporter gene and amygdala activation in response to fearful stimuli Imaging Genetics

21. Structural (CT, MRI, DTI) Neurochemical (MRS, SPECT, PET) Functional (MRI, SPECT, PET) Neuroimaging Clinical Features Genes Gene expression Protein Cells Systems Behaviour Roffman et al., 2005 Disease Differentiation Incidental Findings Translation Stigma Response Sensitivity Commercialization Privacy/ Autonomy Resources Science and Society Imaging Genetics Ethical Considerations Discriminative Power Cumulative Power Tairyan et al., Neuroscience, 2009

22. Functional Frontier:Resting State fMRI • The brain is highly active at rest • Connectivity analyses suggest distributed, large-scale functional networks • Detection of changes in functional connectivity within individuals from a single scan • Disruptions of the networks have been observed in Alzheimer’s, schizophrenia and other disorders of the CNS • Will task-dependent or task-independent resting state fMRI be the first functional frontier for incidental findings?

23. •  Uncertainty in current understanding of the resting state • Heritability of networks •  Anonymization in offline processing • Implications of findings for perception of self and social categories Frontier Challenges

24. Agenda Background Current landscape Ongoing discovery Uncharted territory

25. Uncharted Territory •  Economic analyses beyond aneurysms • Incidental findings in children • Evolving processes for recruitment and consent • Responsibilities and policies in the unregulated non-clinical for-profit sector • Management of incidental findings in cultures in which ownership of health data and consent are shared by communities • Evidence-based policies in a changing health care climate